Background
Growth hormone (GH) replacement therapy has been used in clinical practice for more than 50 years. Initially, only children with GH deficiency (GHD) were treated due to limited availability of the hormone. The development of recombinant human GH (rhGH) increased supply, leading to approval of rhGH therapy in other pediatric indications associated with poor growth [
1]. In adults, GH replacement therapy has been used since the 1990s, with the goal of improving metabolic and psychosocial impairments associated with GHD [
2].
Biosimilar rhGH (Omnitrope®, Sandoz, Kundl, Austria) was approved in Australia in 2004, and by the European Medical Agency (EMA) in 2006, as the world’s first biosimilar rhGH, and has been used in Sweden for over 10 years.
Like all active biological medicines, biosimilar rhGH could induce an immune response with a potential risk that anti-rhGH or neutralizing antibodies may occur during treatment. This has raised some safety and efficacy concerns [
3‐
5]; to ensure safe and effective use of biosimilar medicines, the EMA demands high-quality scientific evidence [
6,
7]. To meet the EMA biosimilar pharmacovigilance requirements, the multicenter, longitudinal, non-interventional, observational PATRO (Patients TReated with Omnitrope®) studies were designed to evaluate the long-term safety and effectiveness of biosimilar rhGH in clinical practice [
8,
9]. Enrollment of Swedish patients in PATRO Children started in 2007 with only few patients registered before 2009; enrollment in PATRO Adults started in 2011.
Here, we present Swedish data from the PATRO Children and Adult databases, focusing on safety, particularly the development of diabetes mellitus and malignancies during the study treatment period. In addition, changes in height variables in children and metabolic effects in adults are reported. Swedish data collected before 2016 were included in previous international reports but the present report includes data for an additional 3 years and more detailed analyses.
Methods
Study design and patient population
The primary aim of the PATRO Children (patients aged 0–18 years) and Adults studies is to collect and analyze data on the long-term safety of biosimilar rhGH in patients treated in routine clinical practice. The primary objective is to follow patients for safety concerns, such as the occurrence of diabetes mellitus or malignancies, and to detect anti-hGH antibodies inducing a lack or loss of effectiveness in pediatric patients. The secondary aims are to assess long-term treatment effectiveness in terms of growth response in children, and the effects on body composition and cardiovascular risk factors in adults.
The designs of both studies have previously been described in detail [
8,
9]. Briefly, children and adults who are receiving treatment with biosimilar rhGH, both rhGH-naïve and those previously treated with another rhGH medicine, are eligible for inclusion. Patients were enrolled consecutively and no formal exclusion criteria were applied. The frequency of visits follows routine clinical practice; no additional visits, tests, or assessments are required as part of the study. In Sweden all patients fulfilling the diagnostic criteria for GHD and without contraindications are offered GH treatment. Biosimilar rhGH dosing is at the discretion of the treating physicians as reported to the PATRO database; information on dose is collected at baseline (entry into the PATRO study) and at least yearly thereafter.
Safety assessments
All adverse events (AEs) and serious AEs (SAEs) were collected, recorded in electronic case report forms (eCRF), and entered into the sponsor’s safety database for the duration of biosimilar rhGH treatment.
Growth evaluation in children
Height and weight were measured at each visit and converted to standard deviation scores (SDS) using the current Swedish growth reference, according to sex and age [
10]. The outcome variables used for evaluation of effectiveness were prepubertal first year gain in height SDS (ΔHSDS) (and if possible due to age of the child, also ΔHSDS 0–2 and 0–3 years) in rhGH-naïve patients. The calculation of prepubertal HSDS included only data from girls before reaching 10 years of age and from boys before reaching 11 years [
11], in order to exclude interference of the pubertal component in the combined average growth reference.
Investigator assessment was used to confirm if patients had reached adult height (AH) or near AH. Attained AH in centimeters was converted to adult HSDS at age 18 years, even if AH was reached at an earlier age. Body mass index (BMI) SDS was derived from our Swedish reference [
12]. Puberty stage was assessed clinically by the investigator, according to standards established by Tanner [
13] and Prader [
14].
BMI, waist circumference, blood lipids, and fasting blood glucose were assessed at treatment start and yearly thereafter during 4 years of treatment.
Laboratory analyses
Anti-hGH antibody determination in children was carried out upon request in routine clinical practice or as requested by the EMA in rhGH-naïve children until 2 years after the start of biosimilar rhGH treatment. Analyses were performed at a single selected laboratory (Q2 Solutions, Valencia, CA, USA). Results were entered according to the sample collection date. Antibodies were measured by using a semi-quantitative radioimmunoassay. Briefly, radio isotope labeled rhGH (125I-rhGH) was incubated at a refrigerated temperature overnight with the serum specimen; antibodies in the specimen bind to the 125I rhGH. The bound/free separation was achieved with 20% polyethylene glycol 8000 and centrifugation. The radioactivity of the pellet remaining in the assay tube was counted in a gamma counter and the response was proportional to the amount of anti-rhGH antibodies present in the specimen. The results were reported in index units calculated from a normal pool. Specimens were considered positive when the index value was > 1.76.
Insulin-like growth factor (IGF)-I μg/L was measured locally at each participating center and SDS values were calculated according to laboratory-performed analyses. Serum high-density lipoprotein (HDL) cholesterol was measured at a local laboratory, and serum concentrations of low-density lipoprotein (LDL) cholesterol were calculated using Friedewald’s formula [
15].
Data collection and statistical analyses
Available auxological data, biochemistry, medical history, and concomitant therapy were recorded in the eCRF. The safety analysis set (SAF) included all patients who had any data documented in the eCRF and who received at least one dose of biosimilar rhGH. The effectiveness analysis set (EFF) is a subset of the SAF and included all patients with a documented height measurement at the start of biosimilar rhGH treatment (baseline) and at least one measurement of height during treatment, at least 60 days after baseline.
Statistical methods included routine descriptive statistics. Continuous parameters (e.g. height, weight, BMI) were presented as the n, mean, and standard deviation (SD). Categorical parameters (e.g. adverse events) were presented as frequency and percentage. The incidence of an AE within a time period was defined as the number of patients who experienced the event divided by the number of patient-years. Patient-years were calculated by period, with each patient contributing only the actual time they were under observation in this period. A bar chart was generated for the proportion and number of naïve and pre-treated Swedish patients. Box plots were generated for rhGH dose and height-derived parameters (e.g. change from baseline in HSDS). Box plots were displayed by re-aligned visits, and pre-treatment and indication status. A time-series graph was generated for height-derived parameters (e.g. HSDS) over 3 years by indication. For effectiveness results, SDS were generated using the relative deviation from the mean value of normally growing children of the same gender and chronological age. Statistical analyses for this study were performed using the software SAS 9.4. The current interim analysis was performed in January 2019 for both studies.
Discussion
Omnitrope® is the world’s first approved biosimilar rhGH and was introduced in Sweden in 2007. This report describes over 10 years of treatment experience in Sweden, collected in routine clinical practice as part of the observational PATRO studies. Until 2016, Swedish data was included in international reports but here we have added three more years of observation and more detailed, individual analyses.
The main aim of the PATRO studies is to follow patients for safety concerns such as the occurrence of diabetes mellitus or malignancies, and to detect anti-hGH antibodies in rhGH treatment-naïve children. The outcomes we report over 10 years are reassuring in terms of safety and effectiveness across both pediatric and adult indications.
In PATRO Children, no diabetes mellitus, impaired glucose tolerance, or malignancy were reported. The most frequent AEs were of mild intensity and did not require discontinuation of rhGH therapy. These findings are consistent with data from previous studies [
9,
16]. Immunogenicity is a potential risk for biological pharmaceuticals, including rhGH [
17], and in theory, the clinical consequence of antibody development might include a loss of efficacy [
18]. The low (i.e. absent) incidence of antibody formation against biosimilar rhGH in the Swedish PATRO Children population confirms earlier results from interventional studies of children with GHD [
16,
19] and is consistent with earlier data from PATRO Children, which included preliminary Swedish data [
9,
20].
The main reasons for changing from rhGH to biosimilar rhGH for pediatric patients were economic. A change of medicine and injection device may require re-education of patients and families in rhGH administration, an often time-consuming process. This could result in inconvenience or even have negative effects on efficacy if adherence is affected, or patients or family members have safety concerns relating to a change in medication [
21]. However, a new injection device may improve compliance due to greater patient acceptability [
22]. In our study, we did not see any negative effects associated with changing to biosimilar rhGH, and reported AEs were mild, supporting earlier analyses that found switching to biosimilar rhGH had no impact on safety [
23,
24].
In PATRO Adults, development of neoplasms and diabetes mellitus was reported in 26 and 4 patients, respectively. Of note, a relationship between development of cancer (in 8 patients) or relapse of pituitary tumor and rhGH treatment was not suspected by the treating physician or study sponsor for any of the patients, consistent with observations in a previous review [
25]. Regarding the onset of diabetes mellitus, rhGH treatment might impair glucose metabolism, especially in obese patients with a family history of diabetes mellitus. However, the prospective KIMS (Pfizer International Metabolic Database) and NordiNet (Novo Nordisk) registers of non-biosimilar rhGH-treated adults, have reported no increase in the incidence of diabetes mellitus type 2 in patients with GHD and a normal BMI, although an increase in fasting blood glucose (within normal limits) is frequently reported [
25,
26]. In PATRO Adults, AEs were mild in severity, transient, and related to the dose of biosimilar rhGH. Frequently observed side effects with rhGH treatment, such as edema, muscle pain, joint stiffness and pain, paraesthesia, carpal tunnel syndrome, and headache, are often caused by fluid retention [
25,
26]. Our present safety data from Swedish patients enrolled in the PATRO Adults study were consistent with previous observations and reports [
25,
26] as most AEs occurred early and were related to fluid retention.
Biosimilar rhGH was effective in the pediatric population, although only a few rhGH-naïve patients attained AH or had reached the pubertal period by the January 2019 interim analysis. Further evaluation of effectiveness will be possible when more patients have completed the study at age 18 years. Among the six patients reported as non-responders, there were no signs of the biosimilar rhGH being ineffective. Only two of the six patients, diagnosed with familial short stature and hypochondroplasia, respectively, could be judged as genuine non-responders according to the Swedish recommendation of a first-year gain in HSDS growth response < 0.5, despite treatment with an adequate rhGH dose within label [
27]. Familial short stature needs careful evaluation, as a good response to rhGH therapy is rarely seen [
28‐
30], a situation that is similar to short patients with fetal alcohol syndrome [
31]. Height velocity may be improved in children with hypochondroplasia with rhGH doses averaging 0.053 (range, 0.022–0.086) mg/kg/day, but responses vary [
32,
33]. Four of the children with low growth response received a lower than recommended rhGH dose. The International TS Consensus Group recommends an initial dose 0.045–0.050 mg/kg/day, increasing to 0.068 mg/kg/day if AH potential is compromised [
34]. For short children born SGA, the range for effect on growth is reported to be wide [
35]. The reported rhGH doses in PATRO Children were lower on average compared with the recommended doses for similar patient groups worldwide [
1,
27]. The Swedish recommendation for rhGH dose in GHD patients is 0.033 mg/kg/day based on studies of the physiology of GH secretion in children [
28]. In Swedish national randomized clinical trials, an rhGH dose of 0.067 mg/kg/day during puberty showed higher growth responses compared with standard doses in children diagnosed with GHD or non-GHD short stature [
29,
30]. In PATRO, use of rhGH doses below those recommended may be explained by caution among physicians in the use of a clinically new drug. In addition, during the introduction of the biosimilar rhGH, a report from the French SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study suggested an increased risk of mortality due to bone tumors and cerebrovascular diseases in patients with GHD, ISS, or SGA treated with rhGH during childhood [
31]. Swedish, Belgian, and Dutch data from the same period did not support this finding [
32]; instead it was shown that size at birth is an important factor [
33]. However, concerns about the consequences of rhGH dosage remain [
1,
34], and the consensus is to use the lowest effective dose if therapy is started.
Another reason for using reduced rhGH doses in the PATRO Children study may be that individual rhGH responsiveness was not considered [
35]. In group analyses, patients with non-GHD-related short stature need a higher dose to attain the same growth response as patients with GHD [
36]. This was shown for prepubertal patients [
36] and was later confirmed for pubertal growth until AH [
29,
30,
37,
38]. The variation in growth response in the SGA group could possibly have been reduced by estimation of responsiveness using a prediction model [
39,
40].
Adult GHD is characterized by abnormal body composition, with more body fat than lean body mass, an adverse lipid profile, and poor quality of life [
2]. Several studies have shown that rhGH treatment improves these variables [
2,
26,
41]. Baseline characteristics for patients in PATRO Adults were similar to previous reports of adults with GHD (i.e. low IGF-I, overweight, and elevated waist circumference) [
2,
26,
41]. Also, consistent with previous studies, we found that BMI and waist size remained stable during treatment with biosimilar rhGH [
2,
26,
41]. Previous studies [
2,
26,
41] have shown a decrease in total and LDL cholesterol, and in agreement with these findings we also observed a decrease in LDL/HDL cholesterol ratio.
Strengths and limitations
A strength of the study is the comprehensive and uniform long-term follow up. Data collected are monitored twice a year by a contract research organization to ensure accuracy. Females represent 50% of the population in PATRO Children, with or without the TS group. This is a positive trend compared with earlier studies from the Swedish national GH register and from Swedish clinical trials [
29,
30].
One limitation of the pediatric part of the study is the short observation time to detect growth until AH. Additionally, the small number of patients with different diagnoses and GHD etiologies results in a heterogeneous cohort, preventing sub-group analyses. It is also a limitation that blood samples were not analyzed centrally. Furthermore, there is a potential selection bias due to enrolment of patients from a few centers. In addition, it was not possible to compare the incidence of AEs reported in the study with the background rate occurring in a Swedish population. Systematic follow up in national databases will improve control, research, and individualization of rhGH treatment.
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